Functionalized biodegradable triclosan monomers and oligomers for controlled release

ABSTRACT

This invention relates to the discovery of functionalized triclosan monomers and oligomers that, when incorporated into a substrate of, or applied as part of a coating to, medical devices and/or consumer products may extend the duration of antimicrobial properties to the medical devices and/or consumer products.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Application No. 60/975,374,filed Sep. 26, 2007, the disclosure of which is hereby incorporatedherein by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to functionalized triclosan monomers andoligomers that, when incorporated into a substrate of, or applied aspart of a coating to, medical devices and/or consumer products mayextend the duration of antimicrobial properties to the medical devicesand/or consumer products.

BACKGROUND OF THE INVENTION

Triclosan is a chlorinated aromatic compound that has ether and phenolgroups. Such phenols reportedly often show anti-bacterial properties.Triclosan may be used in soaps, deodorants, toothpastes mouthwashes, andcleaning supplies and is incorporated in an increasing number ofconsumer products, such as kitchen utensils, toys, bedding, socks, andtrash bags. It has been reportedly shown as effective in reducing andcontrolling bacterial contamination on the hands and on treatedproducts. More recently, it has been reported that showering or bathingwith 2% triclosan is a recommended regime for the decolonization ofpatients whose skin is carrying methicillin resistant Staphylococcusaureus following the successful control of MRSA outbreaks in severalclinical settings.

Triclosan is disclosed as being useful as an antimicrobial agent invarious formulations in the following patents: EP1460089; U.S. Pat. No.6,045,813; U.S. Pat. No. 6,955,827; U.S. Pat. No. 6,224,579; U.S. Pat.No. 6,207,139; U.S. Pat. No. 6,596,657; U.S. Pat. No. 6,780,799; U.S.Pat. No. 3,903,007; U.S. Pat. No. 3,987,797; U.S. Pat. No. 4,024,871;U.S. Pat. No. 5,378,540; U.S. Pat. No. 6,106,505; U.S. Pat. No.6,083,208; US 2004/0185250; US 2006/0091034; US 2002/0028229; WO96/38528; U.S. Pat. No. 4,020,100; EA 0099177.

Certain dental products containing triclosan are described in U.S. Pat.No. 6,207,139 that are reported as having anti-tartar activity.

In U.S. Pat. Nos. 6,596,657 and 6,780,799, Shalaby described the use ofsodium triclosan salt, reported as being useful to impart antimicrobialcharacteristics to fabrics.

In U.S. Pat. No. 3,903,007 Model, et al. the use of 2-acyloxy-triclosanwas disclosed and reported as being useful for detergent compositions.

In U.S. Pat. Nos. 6,106,505 and 6,083,208, Modak et al. describedpolymeric medical articles reportedly comprising synergisticcombinations of the antiinfective agents chlorhexidine and triclosan.

US patent application 20040185250 discloses certain triclosan-containingabsorbable antimicrobial sutures reported having extended antimicrobialproperties. Triclosan was reported to be incorporated into theabsorbable sutures by coating, soaking, soaking and coating of triclosancontaining solutions or adding triclosan into absorbable polymers beforethey are processed into fibers.

Lezdey et al. (US patent application 20020028229) disclosedantimicrobial compositions that reported contain a phenol complex with afilm forming complex of a polycarboxylic acid and a microbicidecontaining at least two quaternary amine groups.

In US patent application 20060091034, Scalzo et al. described a methodfor making an antimicrobial suture, disclosed as comprising the steps ofpositioning an antimicrobial agent source within a package comprising aninner surface, said antimicrobial agent being selected from the groupconsisting of halogenated hydroxyl ethers, acyloxydiphenyl ethers, andcombinations thereof; positioning a medical device within the package;and subjecting the package, the antimicrobial agent source and themedical device to time, temperature and pressure conditions sufficientto vapor transfer an effective amount of the antimicrobial agent fromthe antimicrobial agent source to the medical device, therebysubstantially inhibiting bacterial colonization on the medical device.As an alternative, the disclosure reportedly provided a packaged medicaldevice produced according to the steps of positioning a medical devicewithin a package; exposing the package having the medical device to anantimicrobial agent source; and subjecting the package having themedical device and the antimicrobial agent source to time, temperatureand pressure conditions sufficient to transfer an effective amount ofthe antimicrobial agent from the antimicrobial agent source to themedical device within the package, thereby substantially inhibitingbacterial colonization on the medical device.

While triclosan compounds have various known beneficial uses, theygenerally are insoluble or partially soluble in water or the human bodyand are difficult to hydrolyze. They are also very difficult topolymerize in the phenolic state. As such, there are still unmet needsfor materials with improved properties, in particular those materialshaving improved water compatibility, controlled release, targetedrelease to specific organs, and the like. The present invention isdirected to these and other important ends.

SUMMARY OF THE INVENTION

The present invention in part provides hydrolysable functionalizedtriclosan monomers and oligomers with tunable degradation profile. Incertain embodiments, the hydrolytic degradation of monomers andoligomers of the present invention releases triclosan as such with nochange in native chemical structure.

Applicants have found that triclosan may be functionalized with safe andbiocompatible molecules such as glycolic acid, lactic acid, p-dioxanone,and/or caprolactone monomers. By careful selection of the biocompatiblemolecules, the hydrolysis profiles of these new functionalized triclosancompounds are more highly controllable. Other compound properties thatare favorably affected include increased solubility, improvedbioavailability, improved efficacy, and enhanced functionality.

The functionalization of triclosan using biocompatible molecules such asthose described herein produces a hydrolysable, bioabsorbable compound.This process enhances the native value of triclosan by providing theresultant compound or combination of compounds with a specific,controlled degradation profile or range, enabling the controlled releaseof triclosan over an extended, controllable time range. The differentcontrolled release profiles represent slow, moderate and/or rapidrelease of the active substance (triclosan). In certain embodiments thisrelease may be targeted to one or more specific organs or parts of thebody. The invention described herein greatly extends the usefulness oftriclosan and provides greater control of the bioavailability of thetriclosan while retaining its inherent biological properties.

Because, in certain embodiments, the functionalized triclosan compoundsof the present invention retain the innate properties of the activetriclosan compound, they may be used, in many instances, in applicationswherein triclosan and/or triclosan compounds are typically employed. Forexample, they may serve as enhanced antimicrobial agents that find use,for example, in controlled release preparations, cosmetic applications,and flavors. They may also be employed, for example, in coatings forbiomedical devices, such as stents, absorbable implantable devices,and/or surgical sutures, and/or for biodegradable chewing gum,nutriceuticals, or drug delivery. In addition, the active portion of thefunctionalized triclosan has improved bioavailability and/or increasedsolubility. The compounds of the present invention permit the user tobetter control the degradation and/or target delivery of the activetriclosan component. The compounds may be further reacted and, in manycases, further polymerized, expanding their usefulness.

The present invention also relates to the discovery of functionalizedtriclosan compounds, and the observation that the resultantfunctionalized triclosan compounds and their oligomers have controllabledegradation profiles, releasing the active triclosan component over adesired time range. The compounds may be used alone or in combinationwith with one or more other functionalized triclosan compounds of theinvention as a mixture in order to extend the time range over which theactive ingredient is released. The compounds may also be used incombination with absorbable polymers to further extend their usefulnessby providing still greater variation in, and control of, the degradationor hydrolysis range of the functionalized triclosan compounds in themixture.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides functionalizedtriclosan oligomers of formulas A, B, and/or C:

R[(CH₂)_(f)C(═O)—(Y)_(a)—O—R¹]  A;

R[—(Y)_(a)—O—R¹]_(w)   B;

R¹—O—(Y¹)_(c)—O—(Y)_(d)—O—R¹   C;

wherein:

-   -   each Y is independently:        -   —OCH₂C(═O)— (inverse glycolic ester moiety), —OCH(CH₃)C(═O)—            (inverse lactic ester moiety), —OCH₂CH₂OCH₂C(═O)— (inverse            dioxanone ester moiety), —OCH₂CH₂CH₂CH₂CH₂C(═O)— (inverse            caprolactone ester moiety), —O(CH₂)_(y)C(═O)—, or            —O(CH₂CH₂O)₂OCH₂C(═O)—;    -   each Y¹ is independently:        -   —C(═O)CH₂O— (glycolic ester moiety), —C(═O)CH(CH₃)O— (lactic            ester moiety), —C(═O)CH₂OCH₂CH₂O— (dioxanone ester moiety),            —C(═O)CH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety),            —C(═O)(CH₂)_(m)O—, or —C(═O)CH₂O(CH₂CH₂O)_(n)—;    -   R is a di-, tri, tetra-, penta- or hexaradical derived from        C₁₋₂₅ alkyl, aryl, or aryl-(C₁₋₆alkyl)₁₋₃-, wherein from 1-4 of        the CH₂ groups within the alkyl chain are optionally        independently replaced by O or S atoms, preferably by O atoms,        such that each of said O or S atoms is attached only to carbon        atoms in the alkyl chain, with the proviso that the O or S atoms        are separated from the di-, tri, tetra-, penta- or hexaradical        chain ends by at least one carbon atom and that multiple O or S        atoms in the di-, tri, tetra-, penta- or hexaradical chain must        be separated from each other by at least two carbon atoms; or R        is —[CH₂CH₂O—]_(p)—, wherein p is an integer from about 10 to        about 50;    -   R¹ is:

-   -   each a is independently an integer from about 1 to about 8;    -   each f is independently the integer 0 or 1; with the proviso        that when f is 0, then R is other than —[CH₂CH₂O—]_(p)—;    -   each m and n is independently an integer from about 2 to about        24;    -   w is an integer from about 2 to about 6; and    -   c and d are each an integer from 1 to 5, with the proviso that        the sum of c+d is an integer from about 2 to about 6.

In certain preferred embodiments of formula B oligomers, and/or medicaldevices or medical device coatings thereof comprising the oligomers, thefunctionalized triclosan oligomer has the structure:

In an embodiment, the present invention provides functionalizedtriclosan monomers of formula I:

wherein:

-   -   each Y¹ is independently:        -   —C(═O)CH₂O— (glycolic ester moiety), —C(═O)CH(CH₃)O— (lactic            ester moiety), —C(═O)CH₂OCH₂CH₂O— (dioxanone ester moiety),            —C(═O)CH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety),            —C(═O)(CH₂)_(m)O—, or —C(═O)CH₂O(CH₂CH₂O)_(n)—;    -   R¹ is:

-   -   a is an integer from about 1 to about 8; and    -   each m and n is independently an integer from about 2 to about        24.

In an embodiment, the present invention provides functionalizedtriclosan monomers of formula II:

wherein:

-   -   each X¹ is independently:        -   —CH₂C(═O)O— (glycolic acid moiety), —CH(CH₃)C(═O)O— (lactic            acid moiety), —CH₂CH₂OCH₂C(═O)O— (dioxanone moiety),            —CH₂CH₂CH₂CH₂CH₂C(═O)O— (caprolactone moiety),            —(CH₂)_(y)C(═O)O—, or —(CH₂CH₂O)_(z)CH₂C(═O)O—;    -   R¹ is:

-   -   a is an integer from about 1 to about 8; and    -   each y and z is independently an integer from about 2 to about        24.

In certain preferred embodiments of formula II monomers, and/or medicaldevices or medical device coatings thereof comprising the formula IImonomers, the functionalized triclosan monomers are selected from thegroup consisting of:

In another embodiment, the present invention provides functionalizedtriclosan monomers of formula III:

wherein:

-   -   each Y¹ is independently:        -   —C(═O)CH₂O— (glycolic ester moiety), —C(═O)CH(CH₃)O— (lactic            ester moiety), —C(═O)CH₂OCH₂CH₂O— (dioxanone ester moiety),            —C(═O)CH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety),            —C(═O)(CH₂)_(m)O—, or —C(═O)CH₂O(CH₂CH₂O)_(n)—;    -   R¹ is:

-   -   b is an integer from about 1 to about 8;    -   each m and n is independently an integer from about 2 to about        24; and    -   Q is F, Cl, Br, or I.

In another embodiment, the present invention provides functionalizedtriclosan oligomers of formula IV:

wherein:

-   -   each Y is independently:        -   —OCH₂C(═O)— (inverse glycolic ester moiety), —OCH(CH₃)C(═O)—            (inverse lactic ester moiety), —OCH₂CH₂OCH₂C(═O)— (inverse            dioxanone ester moiety), —OCH₂CH₂CH₂CH₂CH₂C(═O)— (inverse            caprolactone ester moiety), —O(CH₂)_(m)C(═O)—, or            —O(CH₂CH₂O)_(n)OCH₂C(═O)—;    -   each Y¹ is independently:        -   —C(═O)CH₂O— (glycolic ester moiety), —C(═O)CH(CH₃)O— (lactic            ester moiety), —C(═O)CH₂OCH₂CH₂O— (dioxanone ester moiety),            —C(═O)CH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety),            —C(═O)(CH₂)_(m)O—, or —C(═O)CH₂O(CH₂CH₂O)_(n)—;    -   R¹ is:

-   -   a and b are each independently an integer from about 1 to about        8;    -   each m and n is independently an integer from about 2 to about        24.

In another embodiment, the present invention provides functionalizedtriclosan oligomers of formula V:

wherein:

-   -   each Y is independently:        -   —OCH₂C(═O)— (inverse glycolic ester moiety), —OCH(CH₃)C(═O)—            (inverse lactic ester moiety), —OCH₂CH₂OCH₂C(═O)— (inverse            dioxanone ester moiety), —OCH₂CH₂CH₂CH₂CH₂C(═O)— (inverse            caprolactone ester moiety), —O(CH₂)_(m)C(═O)—, or            —O(CH₂CH₂O)_(n)OCH₂C(═O)—;    -   each Y¹ is independently:        -   —C(═O)CH₂O— (glycolic ester moiety), —C(═O)CH(CH₃)O— (lactic            ester moiety), —C(═O)CH₂OCH₂CH₂O— (dioxanone ester moiety),            —C(═O)CH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety),            —C(═O)(CH₂)_(m)O—, or —C(═O)CH₂O(CH₂CH₂O)_(n)—;    -   R is a diradical derived from C₁₋₂₅ alkyl, aryl, or        aryl-(C₁₋₆alkyl)₁₋₃-, wherein from 1-4 of the CH₂ groups within        the alkyl chain are optionally independently replaced by O or S        atoms, preferably by O atoms, such that each of said O or S        atoms is attached only to carbon atoms in the alkyl chain, with        the proviso that the O or S atoms are separated from the        diradical chain must be separated from each other by at least        two carbon atoms; or R is —[CH₂CH₂O—]_(p)—, wherein p is an        integer from about 10 to about 50;    -   R¹ is:

-   -   each b is independently an integer from about 0 to about 8; and    -   each m and n is independently an integer from about 2 to about        24.

The oligomers of formula A of the present invention are prepared byreacting monomers of formula I or their halo derivatives (formula III,wherein b is (a−1) and Q is halo) with linear and/or multi-armed acidsof formula R—(C(═O)OH)_(s), wherein s is an integer from about 2 toabout 6 and where the acids used maybe symmetrical or unsymmetrical,preferably symmetrical or unsymmetrical ether diacids (e.g., seestructures below). Oligomers of formula V are, for example, prepared byreacting monomers of formula III with linear or non-linear, symmetricalor non-symmetrical diacids of formula R—(C(═O)OH)_(s), wherein s is theinteger 2.

In another embodiment, the present invention provides functionalizedtriclosan oligomers of formula VI:

wherein:

-   -   each X is independently:        -   —OC(═O)CH₂— (inverse glycolic acid moiety), —OC(═O)CH(CH₃)—            (inverse lactic acid moiety), —OC(═O)CH₂OCH₂CH₂— (inverse            dioxanone acid moiety), —OC(═O)CH₂CH₂CH₂CH₂CH₂— (inverse            caprolactone acid moiety), —OC(═O)(CH₂)_(y)—, or            —OC(═O)CH₂(OCH₂CH₂)_(z)—.    -   each X¹ is independently:        -   —CH₂C(═O)O— (glycolic acid moiety), —CH(CH₃)C(═O)O— (lactic            acid moiety), —CH₂CH₂OCH₂C(═O)O— (dioxanone moiety),            —CH₂CH₂CH₂CH₂CH₂C(═O)O— (caprolactone moiety),            —(CH₂)_(y)C(═O)O—, or —(CH₂CH₂O)_(z)CH₂C(═O)O—;    -   R is a diradical derived from C₁₋₂₅ alkyl, aryl, or        aryl-(C₁₋₆alkyl)₁₋₃-, wherein from 1-4 of the CH₂ groups within        the alkyl chain are optionally independently replaced by O or S        atoms, preferably by O atoms, such that each of said O or S        atoms is attached only to carbon atoms in the alkyl chain, with        the proviso that the O or S atoms are separated from the        diradical chain ends by at least one carbon atom and that        multiple O or S atoms in the diradical chain must be separated        from each other by at least two carbon atoms; or R is        —[CH₂CH₂O—]_(p)—, wherein p is an integer from about 10 to about        50; or R is a homopolymer or copolymer of glycolide, lactide,        caprolactone, p-dioxanone, or a combination thereof (e.g., M_(n)        of from 100, 200, 300, 400, 500, 600, 700, 800, 900, to 1000);    -   R¹ is:

-   -   each a is independently an integer from about 0 to about 8; and    -   each y and z is independently an integer from about 2 to about        24;    -   with the proviso that when R is a diradical derived from C₁₋₂₅        alkyl, aryl, or aryl-(C₁₋₆alkyl)₁₋₃-, wherein none of the CH₂        groups within the alkyl chain are replaced by O or S atoms, then        at least one of a is an integer from about 1 to about 8.

In another embodiment, the present invention provides functionalizedtriclosan monomers of formula VII:

wherein:

-   -   R¹ is:

In another embodiment, the present invention provides functionalizedtriclosan oligomers of formula VIII:

-   -   wherein:        -   Z is selected from —CH₂—CH₂—, —CH₂—O—CH₂—, and —CH₂—; and        -   R¹ is:

-   -   -   R is a diradical derived from C₁₋₂₅ alkyl, aryl, or            aryl-(C₁₋₆alkyl)₁₋₃-, wherein from 1-4 of the CH₂ groups            within the alkyl chain are optionally independently replaced            by O or S atoms, preferably by O atoms, such that each of            said O or S atoms is attached only to carbon atoms in the            alkyl chain, with the proviso that multiple heteroatoms must            be separated from each other by at least two carbon atoms            and from the diradical chain ends by at least one carbon            atom;

    -   or R is —[CH₂CH₂O—]_(p)—, wherein p is an integer from about 10        to about 50;        -   with the proviso that at least one of Z is —CH₂—O—CH₂—.

As used herein for functionalized triclosan oligomers of formula VIII,when R is —[CH₂CH₂O—]_(p)—, the two oxygen atoms in the moiety “O—R—O”are implicit in the R moiety. For example, the terminal oxygen atoms inthe diradical —O—CH₂CH₂—O—CH₂CH₂—O— (that is, wherein R is—[CH₂CH₂O—]_(p) and p is 2) form part of both the R and the two “O” atomfunctions. Thus when R is R is —[CH₂CH₂O—]_(p)— and p is 2) the oligomerof formula VIII has the formula:

R¹—O—C(═O)-Z-C(═O)—O—CH₂CH₂—O—CH₂CH₂—O—C(═O)-Z-C(═O)O—R¹.

The triclosan-functionalized oligomers of general formulaR[OC(═O)-Z-C(═O)O—R¹]_(f) are prepared, for example, by reaction oftriclosan-functionalized monomers of formula VII with a linear ormultiarmed polyol of general formula R—(OH)_(f) where f is an integerfrom about 2 to about 6. In particular, triclosan-functionalizedoligomers of formula VIII of the present invention are prepared byreaction of triclosan-functionalized monomers of formula VII with alinear on nonlinear, symmetrical or non-symmetrical diol (f is theinteger 2).

In another embodiment, the present invention provides functionalizedtriclosan oligomers of formula IX:

wherein:

-   -   R′ and R″ are each independently R is a diradical derived from        C₁₋₂₅ alkyl, aryl, or aryl-(C₁₋₆alkyl)₁₋₃-, wherein from 1-4 of        the CH₂ groups within the alkyl chain are optionally        independently replaced by O or S atoms, preferably by O atoms,        such that each of said O or S atoms is attached only to carbon        atoms in the alkyl chain, with the proviso that multiple        heteroatoms must be separated from each other by at least two        carbon atoms and from the diradical chain ends by at least one        carbon atom; or R is —[CH₂CH₂O—]_(p)—, wherein p is an integer        from about 10 to about 50; and    -   R¹ is:

In some embodiments, the invention is directed di-, tri-, or polyamidocompounds that are the reaction products of functionalized triclosanoligomers of formula VII:

wherein:

-   -   R¹ is:

biodegradable di- tri-, or polyamines.

In certain preferred embodiments of the di-, tri-, or polyamidocompounds, the biodegradable di- tri-, or polyamine is selected from thegroup consisting of:

wherein n is an integer from about 10 to about 50;

Other embodiments of the present invention are directed to di-, tri-, orpolyamido compounds that are the reaction product of a diacid selectedfrom the group consisting of:

a di- tri-, or polyamine is selected from the group consisting of:

wherein n is an integer from about 10 to about 50;

Certain embodiments of the present invention are directed tocompositions comprising:

1) a functionalized triclosan monomer of formula III:

wherein:

-   -   each Y¹ is independently:        -   —C(═O)CH₂O— (glycolic ester moiety), —C(═O)CH(CH₃)O— (lactic            ester moiety), —C(═O)CH₂OCH₂CH₂O— (dioxanone ester moiety),            —C(═O)CH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety),            —C(═O)(CH₂)_(m)O—, or —C(═O)CH₂O(CH₂CH₂O)_(n)—;    -   R¹ is:

-   -   b is an integer from about 1 to about 8;    -   each m and n is independently an integer from about 2 to about        24; and    -   Q is F, Cl, Br, or I; and        2) an amine acid selected from the group consisting of:

In certain embodiments of the compositions of the present invention, theamine acids are associated with, coordinated to, and/or complexed withthe monomers of formula III. In other embodiments, the monomers offormula III react with amine acids to form the corresponding ammoniumsalt.

In functionalized triclosan monomers and/or oligomers of formula C, theO between the two Y groups depicted as (Y)—O—(Y¹) represents an etherlinkage between the Y and Y¹ groups such that there is only one —O—ether moiety in the chain (Y)—O—(Y¹). By way of example, when Y iscorresponds to —C(═O)CH₂O— (glycolic ester moiety), and Y¹ correspondsto —OCH(CH₃)C(═O)— (inverse lactic ester moiety), the resultant(Y)—O—(Y¹) is —COCH₂O—CH(CH₃)C(═O)—. Similarly, when R is—[CH₂CH₂O—]_(p)— and is connected to (Y¹), the resultant R—(Y¹) is—[CH₂CH₂O—]_(p)—CH(CH₃)C(═O)—, when for example, (Y¹) is—OCH(CH₃)C(═O)—. When R is —[CH₂CH₂O—]_(p)—, p is 3, and X is—OC(═O)CH₂— and R is attached to X in the following manner (R—X), theresultant R—X may be depicted as—O—[CH₂CH₂—O—CH₂CH₂—O—CH₂CH₂—O]—C(═O)CH₂—.

As used herein the term “—[CH₂CH₂O—]_(p)—” refers to an oligoethyleneoxydiradical moiety, with the understanding that both ends of the diradicalbear an oxygen atom. For example, when R is —[CH₂CH₂O—]_(p)— and p is 3,the diradical R maybe depicted as —O—[CH₂CH₂—O—CH₂ CH₂—O—CH₂CH₂—O]—.

In some preferred embodiments of functionalized triclosan monomersand/or oligomers of formula IV, V, or C, Y and Y¹ are derived fromdifferent hydroxyacid or lactone precursors. As non-limiting examples, Ymay be —C(═O)CH₂O— (derived from glycolic acid) is and Y¹ may be—OCH(CH₃)C(═O)— (derived from lactic acid), or Y may be derived fromlactic acid and Y¹ may be derived from caprolactone.

In some preferred embodiments of functionalized triclosan monomersand/or oligomers of formula VI, X and X¹ are derived from differenthydroxyacid or lactone precursors. As non-limiting examples, X may be—CH₂C(═O)O— (derived from glycolic acid) and X¹ may be —OC(═O)CH(CH₃)—(derived from lactic acid), or X may be derived from lactic acid and X¹may be derived from caprolactone.

In other preferred embodiments of functionalized triclosan monomersand/or oligomers of formulas V, VI, VIII, A, or B, R is selected from aC₂₋₁₂ alkyl, phenyl, and phenyl-(C₁₋₆ alkyl)₁₋₃-. In certain preferredembodiments wherein R is alkyl or aryl-(C₁₋₆ alkyl)₁₋₃-, 1-4 of the CH₂groups within the alkyl or aryl-(C₁₋₆alkyl)₁₋₃-chain are optionallyindependently replaced by O or S moieties, such that each of said O or Smoieties is attached only to carbon atoms in the alkyl chain, oralternatively, in moieties to at least one alkyl chain carbon atom, theother being either an aryl ring carbon atom or a second alkyl chaincarbon atom. In some preferred embodiments, multiple heteroatoms must beseparated from each other by at least two carbon atoms and from the di-,tri, tetra-, penta- or hexaradical chain ends by at least one carbonatom;

Alternatively in some preferred embodiments, when R is alkyl, it is morepreferably (CH₂), (CH₂)₃, CH(CH₂)₃, C(CH₂)₄, or C(CH₂CH₃)(CH₂)₃. Instill other preferred embodiments, R is (CH₂)₃, and wherein the C-2 CH₂group within the (CH₂)₃ chain is optionally replaced by an O moiety. Inyet other preferred embodiments, R is (CH₂)₂, (CH₂)₃, (CH₂)₄, (CH₂OCH₂),or (CH₂CH₂OCH₂CH₂). In still other preferred embodiments, R is(CH₂CHCH₂) when w is 3, or (C(CH₂)₄) when w is 4.

In other preferred embodiments of functionalized triclosan monomersand/or oligomers of formula IX, R′ and R″ are each independently C₂₋₁₂alkyl, phenyl, and phenyl-(C₁₋₆ alkyl)₁₋₃-. In certain preferredembodiments wherein R is alkyl or aryl-(C₁₋₆ alkyl)₁₋₃-, 0-3 of the CH₂groups within the alkyl chain are optionally independently replaced by Oor S moieties, such that each of said O or S moieties is attached onlyto carbon atoms in the alkyl chain. Alternatively in some preferredembodiments, when R is alkyl, it is more preferably (CH₂), (CH₂)₃,CH(CH₂)₃, C(CH₂)₄, or C(CH₂CH₃)(CH₂)₃. In still other preferredembodiments, R is (CH₂)₃, and wherein the C-2 CH₂ group within the(CH₂)₃ chain is optionally replaced by an O moiety. In yet otherpreferred embodiments, R is (CH₂)₂, (CH₂)₃, (CH₂)₄, (CH₂OCH₂), or(CH₂CH₂OCH₂CH₂). In still other preferred embodiments, R is (CH₂CHCH₂)when w is 3, or (C(CH₂)₄) when w is 4.

In some other preferred embodiments of functionalized triclosan monomersand/or oligomers of formulas I, II, IV, VI, A, or B, each a isindependently an integer from about 0 to about 3, more preferably fromabout 1 to about 3.

In some embodiments of the invention, each a is independently an integerfrom about 0 to about 8. In certain preferred embodiments at least one ais an integer from about 1 to about 8, more preferably about 2 to about8. Alternatively preferred, each a is an integer from about 1 to about8.

In some other preferred embodiments of functionalized triclosan monomersand/or oligomers of formulas III, IV, or V, each b is independently aninteger from about 0 to about 3, more preferably from about 1 to about3.

In some embodiments of the invention, each b is independently an integerfrom about 0 to about 8. In certain preferred embodiments at least one bis an integer from about 1 to about 8, more preferably about 2 to about8. Alternatively preferred, each b is an integer from about 1 to about8.

In certain other preferred embodiments of oligomers or pharmaceuticallyacceptable salts thereof of formulas A or B, w is an integer from about2 to about 4.

In still other preferred embodiments functionalized triclosan monomersand/or oligomers of formula II or VI, each X is independently—OC(═O)CH₂—, —OC(═O)CH(CH₃)—, —OC(═O)CH₂OCH₂CH₂—, or—OC(═O)CH₂CH₂CH₂CH₂CH₂—; more preferably —OC(═O)CH₂— or —OC(═O)CH(CH₃)—.

In some other preferred embodiments of functionalized triclosan monomersand/or oligomers of formula VI, each X¹ is independently —CH₂C(═O)O—,—CH(CH₃)C(═O)O—, —CH₂CH₂OCH₂C(═O)O—, or —CH₂CH₂CH₂CH₂CH₂C(═O)O—, morepreferably —CH₂C(═O)O— or —CH(CH₃)C(═O)O—.

In some preferred embodiments of functionalized triclosan monomersand/or oligomers of formulas I, III, IV, V, A, B, or C, each Y isindependently —OCH₂C(═O)—, —OCH(CH₃)C(═O)—, —OCH₂CH₂OCH₂C(═O)—, or—OCH₂CH₂CH₂CH₂CH₂C(═O)—, more preferably —OCH₂C(═O)— or —OCH(CH₃)C(═O)—.

In certain preferred embodiments of oligomers or pharmaceuticallyacceptable salts thereof of formula IV, V, or C, each Y¹ isindependently —C(═O)CH₂O—, —C(═O)CH(CH₃)O—, —C(═O)CH₂OCH₂CH₂O—, or—C(═O)CH₂CH₂CH₂CH₂CH₂O—; more preferably —C(═O)CH₂O— or —C(═O)CH(CH₃)O—.

In other preferred embodiments of functionalized triclosan monomersand/or oligomers of formula III, Q is preferably Cl, Br, or I, morepreferably Cl or Br, with Cl being even more preferred.

In certain other preferred embodiments of functionalized triclosanmonomers and/or oligomers of formula C or F, c and d are each 1, 2, or3; more preferably both c and d are 1, or they are both 2, or they areboth 3.

Examples of linear and branched biologically active and biologicallynon-active amines that may be useful in the present invention includejeffamines, spermidine, spermine, and putrescine as well asbiodegradable amines including but not limited to those shown in FIG. 1below.

Examples of linear and branched amine acids include but are not limitedto those shown in FIG. 2.

In other embodiments, the present invention provides polymers containingpendant functionalized triclosan groups. These polymers may be obtained,for example, by reaction of functionalized triclosan monomers of formulaIII of the present invention with linear and branched polymers havingpendant acid groups such as polyacrylic acid and polymethacrylic acid bydisplacement of the moiety Q in formula III monomers by the carboxylatefunctionality of the polymers having pendant acid groups.

In other embodiments, the present invention provides modifiedbiologically active compounds formed by reacting a biologically activesubstance (e.g., a drug) containing at least one OH, CO₂H, or aminegroup (e.g., NH₂ or tertiary amine) with a functionalized triclosanmonomer of Formula II or III. In certain embodiments, the biologicallyactive substances compounds are associated with, coordinated to, and/orcomplexed with the monomers of formula III. In other embodiments, themonomer of formula III reacts with the biologically active substance toform a covalent bond between the two moieties, such as an ester, etheror amide bond, for example.

In other embodiments, the present invention provides oligomericquaternary ammonium compounds. These compounds may be obtained, forexample, by reaction of functionalized triclosan monomers of formula IIIof the present invention with tertiary amine-containing biologicallyactive substances, such as Lidocaine and Lidofenin, through displacementof the moiety Q in formula III monomers by the amine functionality ofthe tertiary amine-containing biologically active substances.

Examples of biologically active compounds useful in certain embodimentsinclude phenolic compounds such as phenols and/or naphthols, indoles,acetophenones, benzophenones, coumarins, furanocoumarins, alkaloids,catechins, chromones, chalcones, flavonoids or bioflavonoids,isoflavones, drugs containing phenolic groups, and/or natural productscontaining phenolic groups.

Examples of biologically active dihydroxy compound that maybe used toprepare a polymer of the present invention include Adrenalone,Alfuzosin, Alibendol, Amrubicin, Apomorphine, Bamethan, Benzquinamide,Bevantolol, Bifluranol, Bisacodyl, Brodimoprim, Bunazosin, Bupheniode,Carbidopa, Carbuterol, Cyclofenil, Cyclovalone, Daunorubicin,Dichlorophen, Dienestrol, Diethylstilbestrol, Dimestrol, Dithranol,Donepezil, Doxefazepam, Doxorubicin, Entacapone, Epinepheine,Epirubicin, Esomeprazole, Etamivan, Etamsylate, Etilefrine, Ezetimibe,Fenticlor, Fluorescein, Folescutol, Formoterol, Gefitinib, Hexestrol,Hexylresorcinol, Hydroxyethyl salicylate, Ifenprodil, Isoetarine,Isoxsuprine, Itopride, HCl, Khellin, Labetalol, Mitoxantrone,Morclofone, Moxaverine, Normolaxol, Omeprazole, Oxilofrine, Oxepertine,Phenacaine, Phenolphthalein, Prazosin, Tolcapone, Vesnarinone, andVetradutine.

Examples of biologically active hydroxy/amino compounds that may be usedto prepare a polymer of the present invention include Amisulpride,Amodiaquine, Amosulalol, Amoxicillin, Amsacrine, Azacyclonol,Bromopride, Carvedilol, Cefprozil, Cinitapride, Clebopride, Clenbuterol,Ethoxzolamide, Nadoxolol, D-Norpseudoephedrine, and paracetamol.

Examples of biologically active dicarboxylic acid compounds that may beused to prepare a polymer of the present invention include Adipiodone,Cromoglicic acid, Eprosartan, Iocarmic acid, Iodoxamic acid, Ioglycamicacid, Iotroxic acid, Nedocromil.

Examples of biologically active hydroxy/carboxylic acid compounds thatmay be used to prepare a polymer of the present invention includeAcemetacin, Bentiromide, Cinmetacin, Clometacin, Diflunisal, Fendosal,Indometacin, Iophenoic acid, Naproxen, Repaglinide, Salazosulfapyridine,Salicylic Acid, Salsalate, and Sarpogrelate.

Examples of biologically active hydroxyl-acids that may be useful in thepresent invention include but not limited to 4-hydroxycinnamic acid,Caffeic acid, Chlorogenic acid, Ferulic acid, Sinapinic acid, Vanillicacid, Acemetacin, Bentiromide, Cinmetacin, Clometacin, Diflunisal,Fendosal, Indometacin, Iophenoic acid, Naproxen, Repaglinide,Salazosulfapyridine, Salicylic Acid, Salsalate, and Sarpogrelate.

Examples of biologically active amino/carboxylic acid compounds that maybe used to prepare a polymer of the present invention includeAceclofenac, Acediasulfone, Alminoprofen, Amlexanox, Anileridine,Baccofen, Balsalazide sodium, Benzocaine, Bumetanide, Carprofen,Carzenide, Diclofenac, Flufenamic acid, Furosemide, Iobenzamic acid,Iocetamic acid, and Mefenamic acid.

Some structures of biologically active compounds bearing hydroxylfunctional groups useful in present invention are shown below in FIG. 3.

Examples of biologically active compounds bearing carboxylic acidfunctional groups include but are not limited to Acemetacin,Aceclofenac, Acediasulfone, Adipiodone, Alminoprofen, Amlexanox,Anileridine, Baccofen, Balsalazide sodium, Bentiromide, Benzocaine,Bumetanide, Carprofen, Carzenide, Cinmetacin, Clometacin, Cromoglicicacid, Diclofenac, Diflunisal, Eprosartan, Fendosal, Flufenamic acid,Furosemide, Indometacin, Iobenzamic acid, Iocarmic acid, Iocetamic acid,Iodoxamic acid, Ioglycamic acid, Iophenoic acid, Iotroxic acid,Mefenamic acid, Naproxen, Nedocromil, Repaglinide, Salazosulfapyridine,Salicylic Acid, Salsalate, and Sarpogrelate.

Some structures of biologically active compounds bearing carboxylfunctional groups that may be useful in present invention are shownbelow in FIG. 4.

The rate of hydrolysis of functionalized triclosan monomers andoligomers will depend upon a number of factors, including thefunctionalization species used and the number of repeating units offunctionalization species present on the functionalized triclosanmonomers and oligomers (e.g., 1-6). Glycolic acid modified triclosanshould hydrolyze faster than dioxanone modified one, where as lacticacid and caprolactone modified triclosan should take much longer tohydrolyze than glycolic acid and dioxanone modified triclosan.Furthermore, it is expected that the rate of hydrolysis will increasewith the increase in the value of a and b. Thus, the desired time rangemay be obtained by altering the number of repeating units and type offunctionalization species used to functionalize triclosan.

The present invention also provides blends or monomers and/or oligomerscomprising one or more of the functionalization monomeric or oligomericspecies with triclosan.

The present invention also provides polymer compositions comprising oneor more of the functionalized monomers, oligomers, or di-, tri-, orpolyamido compounds that are functionalized with triclosan.

In some other embodiments of the present invention, the inventivepolymer compositions may be used as pharmaceutical carriers in a drugdelivery matrix. The matrix is formed by mixing the polymer with atherapeutic agent. A vast variety of different therapeutic agents may beused in conjunction with the polymers of the invention. In general,therapeutic agents administered via the pharmaceutical compositions ofthe invention include, without limitation: antiinfectives such asantibiotics and antiviral agents; analgesics and analgesic combinations;anorexics; antihelmintics; antiarthritics; anti-asthmatic agents;anticonvulsants; antidepressants; antidiuretic agents; antidiarrheals;antihistamines; antiinflammatory agents; antimigraine preparations;antinauseants; antineo-plastics; antiparkinsonism drugs; antipruritics;antipsychotics; antipyretics, antispasmodics; anticholinergics;sympathomimetics; xanthine derivatives; cardiovascular preparationsincluding calcium channel blockers and beta-blockers such as pindololand antiarrhythmics; antihypertensives; diuretics; vasodilatorsincluding general coronary, peripheral and cerebral; central nervoussystem stimulants; cough and cold preparations, including decongestants;hormones such as estradiol and other steroids, includingcorticosteroids; hypnotics; immunosuppressives; muscle relaxants;para-sympatyholytics; psychostimulants; sedatives; and tranquilizers;and naturally derived or genetically engineered proteins,polysaccharides, glycoproteins or lipoproteins.

The drug delivery matrix may be administered in any suitable dosage formsuch as oral, parenteral, subcutaneously as an implant, vaginally or asa suppository. Matrix formulations containing polymers of the inventionmay be formulated by mixing one or more therapeutic agents with thepolymer. The therapeutic agent may be present as a liquid, a finelydivided solid, or any other appropriate physical form. Typically, thematrix will include one or more additives, e.g., nontoxic auxiliarysubstances such as diluents, carriers, excipients, stabilizers or thelike. However, the presence of such additives is entirely optional.Other suitable additives may be formulated with the polymers of thisinvention and pharmaceutically active agent or compound, however, ifwater is to be used it should be added immediately beforeadministration.

Compositions comprising monomers and oligomers of the present invention,for example, those in a drug delivery matrix, may be suitable foradministration via a route selected from oral, enteral, parenteral,topical, transdermal, ocular, vitreal, rectal, nasal, pulmonary, andvaginal.

Functionalized triclosan monomers and oligomers of the presentinvention, for example, those in a drug delivery matrix, have morecontrollable hydrolysis profiles, improved bioavailability, improvedefficacy, and enhanced functionality. They may be used for applications,including biomedical applications, foodstuffs, cosmetics, medicaments,coatings and other uses readily apparent to one skilled in the art.Additional examples of drug delivery matrices, as well as the manner ofproviding and use of such matrices and may be found in PatentPublications US2006/0172983 and/or US2007/0251831, the disclosures ofwhich are hereby incorporated herein by reference, in their entireties.

In other aspects of the present invention some functionalized triclosanmonomers and oligomers of the present invention are further manufacturedinto formulations suitable for oral, rectal, parenteral (for example,subcutaneous, intramuscular, intradermal, or intravenous), transdermal,vitreal or topical administration. The most suitable route in any givencase will depend on the nature and severity of the condition beingtreated and on the nature of the particular active compound that isbeing used. The formulations of a pharmaceutical composition aretypically admixed with one or more pharmaceutically or veterinaryacceptable carriers and/or excipients as are well known in the art.

Formulations suitable for oral administration may be presented indiscrete units, such as capsules, cachets, lozenges, or tablets, eachcontaining a predetermined amount of the active compound; as a powder orgranules; as a solution or a suspension in an aqueous or non-aqueousliquid; or as an oil-in-water or water-in-oil emulsion.

Formulations containing functionalized triclosan monomers and oligomersof the present invention suitable for parenteral administrationconveniently comprise sterile aqueous preparations of the activecompounds, where preparations are preferably isotonic with the blood ofthe intended recipient.

Formulations containing functionalized triclosan monomers and oligomersof the present invention suitable for rectal administration arepreferably presented as unit dose suppositories.

Formulations containing functionalized triclosan monomers and oligomersof the present invention suitable for ocular or vitreal administrationmay be presented as bioabsorbable coatings for implantable medicaldevices, injectables, liquids, gels or suspensions.

Formulations or compositions containing functionalized triclosanmonomers and oligomers of the present invention suitable for topicaladministration to the skin preferably take the form of an ointment,cream, lotion, paste, gel, spray, aerosol, or oil. Examples of carriersthat conventionally used include Vaseline, lanoline, polyethyleneglycols, alcohols, and combination of two or more thereof.

Formulations containing functionalized triclosan monomers and oligomersof the present invention suitable for transdermal administration may bepresented as discrete patches adapted to remain in intimate contact withthe epidermis of the recipient for a prolonged period of time.

The functionalized triclosan monomers and oligomers of the presentinvention are suitable for a wide range of devices and coatings,especially those where the antibacterial properties of triclosan are ofbenefit, including but not limited to medical devices and medical devicecoatings, surgical suture coatings, staple coatings, orthopedic devicecoatings, fabric coatings, surgical mesh coatings, clip coatings, stentcoatings, needle coatings, catheters, and catheter coatings. Some otherexamples of coatings and/or devices within the ambit of the inventionare described in Patent Publication US2006/0188547, the disclosure ofwhich is hereby incorporated herein by reference, in its entirety.

In certain other embodiments, the polymer compositions of the presentinvention are used to coat a surface of a surgical article to enhancelubricity of the coated surface. The compositions may be applied as acoating using conventional techniques. For example, the polymercompositions may be solubilized in dilute solution of volatile organicsolvent, e.g. acetone, methanol, ethyl acetate or toluene, and thearticle or medical device immersed in the solution to coat its surface.Once the surface is coated, the surgical article or device is removedfrom the solution where it maybe dried at an elevated temperature untilsolvent and any residual reactants are removed.

Numerous surgical articles (including but not limited to endoscopicinstruments) may be coated with the polymer compositions of thisinvention to improve the surface properties of the article or device.Preferably, the surgical articles include surgical sutures, stents andneedles. More preferably, the surgical article is a suture, still morepreferably a suture attached to a needle. In some preferred embodiments,the suture is a synthetic absorbable suture. These sutures are derived,for example, from homopolymers and copolymers of lactone monomers suchas glycolide, lactide, .epsilon.-caprolactone, 1,4-dioxanone, andtrimethylene carbonate. In some embodiments, the preferred suture is abraided multifilament suture composed of polyglycolide orpoly(glycolide-co-lactide).

The amount of coating polymer to be applied on the surface of a braidedsuture maybe readily determined empirically, and will depend on theparticular copolymer and suture chosen. Ideally, the amount of coatingcopolymer applied to the surface of the suture may range from about 0.5to about 30 percent of the weight of the coated suture, more preferablyfrom about 1.0 to about 20 weight percent, most preferably from 1 toabout 5 percent by weight.

Sutures coated with the polymers of this invention are desirable incertain embodiments because they have a more slippery feel, thus makingit easier, in some instances, for the surgeon to slide a knot down thesuture to the site of surgical trauma. In addition, the suture is morepliable, and therefore is easier for the surgeon to manipulate duringuse.

In other embodiments of the present invention where the article is ametal stent, the amount of coating applied to the surface of the articleis an amount which creates a layer with a thickness ranging preferablybetween about 2 to about 20 microns on the stent, more preferably about4 to about 8 microns.

In other embodiments of the present invention where the article is asurgical needle, the amount of coating applied to the surface of thearticle is an amount which creates a layer with a thickness rangingpreferably between about 2 to about 20 microns on the needle, morepreferably about 4 to about 8 microns.

The compounds and/or compositions of the present invention may beprepared in a number of ways well known to those skilled in the art. Thecompounds maybe synthesized, for example, by the methods describedbelow, or variations thereon as appreciated by the skilled artisan. Allprocesses disclosed in association with the present invention arecontemplated to be practiced on any scale, including milligram, gram,multigram, kilogram, multikilogram or commercial industrial scale.

Examples of functionalized triclosan monomers and oligomers of thepresent invention are provided for some embodiments of the currentinvention. It maybe extended to other species. This selection is notmeant to limit the scope of the invention in any way. Other variationsin the procedure may be readily apparent to those skilled in the art.

EXAMPLES

Example 1 [5-Chloro-2-(2,4-dichloro-phenoxy)-phenoxy]-acetic acid methylester

To a mixture of triclosan (50 grams, 173 mmol), anhydrous K₂CO₃ (100grams, 723 mmol), sodium iodide (10 grams, 66.7 mmol) and disodiumphosphate (10 grams, 70 mmol) in anhydrous acetone (500 mL) was addedmethyl chloro acetate (30 grams, 276 mmol). The reaction mixture wasrefluxed for 16 hours. Acetone was distilled and water (600 mL) wasadded. Crude 1 was extracted into ethyl acetate, dried over Na₂SO₄,distilled and purified by column chromatography on silica gel usinghexane as eluant to give pure 1 (45 grams, 72.1%) as a white powder.m.p: 52-53° C. ^(I)HNMR (CDCl₃) δ 3.78(s, 3H, ester), 4.65 (s, 2H,OCH₂),6.72(d,1H,Ar), 6.88(m,2H,Ar), 6.92(m,1H,Ar), 7.10(m,1H,Ar),7.42(s,1H,Ar).

Example 2 2-[5-Chloro-2-(2,4-dichloro-phenoxy)-phenoxy]-propionic acidmethyl ester

To a mixture of triclosan (50 grams, 173 mmol), anhydrous K₂CO₃ (100grams, 723 mmol), sodium iodide (10 grams, 66.7 mmol) and disodiumphosphate (10 grams, 70 mmol) in anhydrous acetone (500 mL) was addedmethyl 2-chloro propionate (32.25 grams, 263 mmol). The reaction mixturewas refluxed for 24 hours. Acetone was distilled and water (600 mL) wasadded. Crude 2 was extracted into ethyl acetate, dried over Na₂SO₄,distilled and purified by column chromatography on silica gel usinghexane as eluant to give pure 2 (35 grams, 54%) as a syrup. ^(I)HNMR(CDCl₃) δ 1.48(d,3H,CH₃), 3.75(s, 3H, ester), 4.72 (q,1H,O—CH),6.74(d,1H,Ar), 6.90(m,3H,Ar), 7.12(dd,1H,Ar), 7.42(d,1H,Ar).

Example 3 6-[5-Chloro-2-(2,4-dichloro-phenoxy)-phenoxy]-hexanoic acidmethyl ester

To a mixture of triclosan (50 grams, 173 mmol), anhydrous K₂CO₃ (100grams, 723 mmol), sodium iodide (10 grams, 66.7 mmol) and disodiumphosphate (10 grams, 70 mmol), in anhydrous acetone (500 mL) was addedmethyl 6-bromo hexanoate (55 grams, 263 mmol). The reaction mixture wasrefluxed for 30 hours. Acetone was distilled and water (600 mL) wasadded. Crude 3 was extracted into ethyl acetate, dried over Na₂SO₄,distilled and purified by column chromatography on silica gel usinghexane as eluant to give pure 3 (60 grams 90%) as a syrup. ^(I)HNMR(CDCl₃) δ 1.24(m,2H,CH₂), 1.58(m,2H,CH₂), 1.64(m,2H,CH ₂),2.24(t,2H,CH₂), 3.65(s,3H, ester), 3.92 (t,2H,OCH₂)), 6.60(d,1H,Ar),6.92(m,2H,Ar), 6.96(d,1H,Ar), 7.05(d,1H,Ar), 7.42(s,1H,Ar).

Example 4 Benzyloxy-acetic acid 5-chloro-2-(2,4-dichloro-phenoxy)-phenylester

To a mixture of triclosan (7.53 grams, 26 mmol) and triethylamine (8.2grams, 81 mmol) in acetone (50 mL) at 0° C. was added benzyloxy acetylchloride (10 grams, 54.2 mmol) drop wise. The reaction mixture wasstirred at room temperature for 18 hours. Solids were filtered off andpoured onto cold water (100 mL). Crude 4 was extracted into chloroform,washed with 5% sodium bicarbonate solution (2×50 mL), and water (2×50mL). The chloroform layer was dried over sodium sulphate and distilledoff to get crude 4.

Example 5 Hydroxy-acetic acid 5-chloro-2-(2,4-dichloro-phenoxy)-phenylester

Benzyloxy-acetic acid 5-chloro-2-(2,4-dichloro-phenoxy)-phenyl ester 4(5 grams) was dissolved in methanol (50 mL) in a pressure vessel,palladium on carbon (5%, 5 grams) was added and the mixture was stirredunder an atmosphere of hydrogen (4 Kg) for 4 hours. The catalyst wasremoved by filtration and the methanol was distilled off to yield crude5.

Example 6 [5-Chloro-2-(2,4-dichloro-phenoxy)-phenoxy]-acetic acid

[5-Chloro-2-(2,4-dichloro-phenoxy)-phenoxy]-acetic acid methyl ester 1(50 grams, 138.3 mmol) was added to 1.7 N—NaOH (150 mL) solution andheated to 90° C. for 2 hours on a water bath. The reaction mixture wascooled to 5° C., the pH of the reaction mixture was adjusted to 2 usinga 3N-hydrochloric acid. The precipitate was filtered off to give crude6, which was dried and recrystallised from a mixture of ethylacetate:hexane (1:6) to get pure 6 (23 grams, 47.9%) as white powder.m.p: 127-129° C. ¹H NMR (CDCl₃) δ 4.52(s,2H,CH₂), 6.36(bs,1H,COOH),6.76(d,1H,Ar), 6.86(m,3H,Ar), 7.10(cl,1H,Ar), 7.40(s,1H,Ar).

Example 7 [5-Chloro-2-(2,4-dichloro-phenoxy)-phenoxy]-acetic acidmethoxy carbonyl methyl ester

To a solution of [5-Chloro-2-(2,4-dichloro-phenoxy)-phenoxy]-acetic acid6 (20 grams, 57.55 mmol) and triethylamine (9 grams, 88.94 mmol) indimethylformamide (40 mL) was added methyl chloro acetate (8 grams,73.71 mmol). The solution was heated at 70° C. for 1 hour. The solidswere filtered off; the organic phase was poured onto ice (150 grams),extracted into ethyl acetate, washed with 5% sodium bicarbonate (2×50mL) and water (2×50 mL). The ethyl acetate layer was then dried oversodium sulphate and ethyl acetate was distilled off to yield crude 7.The crude 7 was purified by recrystallisation using a mixture of ethylacetate:hexane (1:6) to get pure 7 (17 grams, 70.4%) as off-whitepowder. m.p: 70-72° C. ¹H NMR (CDCl₃) δ 3.80(s,3H,Ester), 4.68(s,2H,CH₂)4.76(s,2H,CH₂), 6.72(d,1H,Ar), 6.92(m,3H,Ar), 7.12(dd,1H,Ar),7.42(d,1H,Ar).

Example 82-{2-[5-Chloro-2-(2,4-dichloro-phenoxy)-phenoxy]-acetoxy}-propionic acidmethyl ester

To a solution of [5-Chloro-2-(2,4-dichloro-phenoxy)-phenoxy]-acetic acid6 (15 grams, 43.16 mmol) and triethyl amine (6.5 grams, 64.23 mmol) indimethylformamide (30 mL) was added methyl 2-chloro propionate (5.8grams, 47.32 mmol). The solution was heated at 70° C. for 4 hours. Thesolids were filtered off, the organic phase was poured onto ice (150grams), extracted into ethyl acetate washed with 5% sodium bicarbonate(2×50 mL) and water (2×50 mL). The ethyl acetate layer was then driedover sodium sulphate and ethyl acetate was distilled off to yield crude8. The crude 8 was purified by column chromatography over silica gelusing a mixture of hexane:ethyl acetate (7:3) to get pure 8 (14 grams,74.8%) as a light yellow syrup. ¹H NMR (CDCl₃) δ 1.50 (d,3H,CH₃), 3.75(s,3H,Ester), 4.75 (s,2H,CH₂), 5.16 (q,1H,CH), 6.75 (d,1H,Ar), 6.95(m,3H,Ar), 7.10 (d,1H,Ar), 7.40 (s,1H,Ar).

Example 9 2-[5-Chloro-2-(2,4-dichloro-phenoxy)-phenoxy]-propionic acid

2-[5-Chloro-2-(2,4-dichloro-phenoxy)-phenoxy]-propionic acid methylester 2 (65 grams, 173.10 mmol) was added to 1.7N—NaOH (195 mL)solution. The solution was heated at 90° C. for 2 hours on a water bath.The reaction mixture was cooled to 5° C. and the pH of the reactionmixture was adjusted to 2 with 3N-hydrochloric acid and filtered to givecrude 9, which was dried and recrystallised from a mixture of ethylacetate:hexane (1:6) to get pure 9 (49 grams, 78.4%) as a white powder.m.p: 67-69° C. ¹H NMR (CDCl₃) δ 1.60(d,3H,CH₃), 4.90(q,1H,CH),6.80(d,1H,Ar), 6.90(d,1H,Ar), 7.00(m,2H,Ar), 7.18(d,1H,Ar),7.50(s,1H,Ar), 8.56(bs,1H,COOH).

Example 10 2-[5-Chloro-2-(2,4-dichloro-phenoxy)-phenoxy]-propionic acid1-methoxycarbonyl-ethyl ester

To a solution of 2-[5-Chloro-2-(2,4-dichloro-phenoxy)-phenoxy]-propionicacid (50 grams, 138.31 mmol) and triethyl amine (22.6 grams, 223.34mmol) in dimethylformamide (100 mL) was added methyl 2-chloro propionate(21.3 grams, 174.23 mmol). The solution was heated at 70° C. for 7hours. The solids were filtered off and the organic phase was poured onice water (250 mL), extracted with ethyl acetate (3×100 mL) followed bywashing with 5% sodium bicarbonate (2×50 mL) and water (2×50 mL). Theethyl acetate layer was then dried over sodium sulphate and ethylacetate was distilled off to yield crude 10. The crude 10 was purifiedby column chromatography on silica gel using hexane:ethyl acetate (9:1)to get pure 10 (40 grams, 64.6%) as a light yellow syrup. ¹H NMR (CDCl₃)δ 1.58(m,6H,CH₃), 3.72(d,3H,Ester), 4.80(m,1H,CH), 5.16(m,1H,CH),6.80(m,1H,Ar), 6.98(m,3H,Ar), 7.10(m,1H,Ar), 7.42(s,1H,Ar).

Example 11 2-[5-Chloro-2-(2,4-dichloro-phenoxy)-phenoxy]-propionic acidmethoxy carbonyl methyl ester

To a solution of 2-[5-Chloro-2-(2,4-dichloro-phenoxy)-phenoxy]-propionicacid (35 grams, 96.81 mmol) and triethyl amine (13 grams, 128.47 mmol)in dimethylformamide (70 mL) was added methyl chloroacetate (12.6 grams,116.10 mmol). The solution was heated at 70° C. for 8 hours. The solidswere filtered off; the organic phase was poured on ice water (200 mL),extracted with ethyl acetate (3×75 mL) followed by washing with 5%sodium bicarbonate (2×50 mL) and water (2×50 mL). The ethyl acetatelayer was then dried over sodium sulphate and ethyl acetate wasdistilled off to yield crude 11. The crude 11 was purified by columnchromatography on silica gel using chloroform as eluant to get pure 11(20 grams, 47.6%) as a light yellow syrup. ¹H NMR (CDCl₃)δ1.55(d,3H,CH₃), 3.74(s,1H,Ester), 4.64(s,2H,CH₂), 4.82(q,1H,CH),6.74(d,1H,Ar), 6.96(m,3H,Ar), 7.10(dd,1H,Ar), 7.42(d,1H,Ar).

Example 12 (Control Sample) Octanedioic acidbis-[5-chloro-2-(2,4-dichloro-phenoxy)-phenyl]ester

A solution of triclosan (17.4 grams, 60.09 mmol), suberic acid (5 grams,28.70 mmol) and thionyl chloride (12.23 grams, 102.77 mmol) was refluxedat 80° C. for 24 hours. Excess thionyl chloride was distilled off andthe product was taken in ethyl acetate followed by washing with 5%sodium bicarbonate solution. The ethyl acetate layer was then dried oversodium sulphate. The dried ethyl acetate layer was treated withcharcoal. 80% of the ethyl acetate was distilled off and the rest of itwas precipitated in hexane. The precipitate was filtered and dried toget 11 grams of 12 as a white powder with the m.p of 81-83° C.Analytical sample was prepared by recrystallisation from a mixture ofethyl acetate:hexane (1:6). m.p: 83-85° C. Mass: M+H₂O=735.5. ¹H NMR(CDCl₃) δ 1.32(t,4H,CH₂), 1.61 (t,4H,CH₂), 2.44(t,4H,CH₂),6.84(m,4H,Ar), 7.16(m,6H,Ar), 7.43(s,2H,Ar).

Hydrolysis Dimer 500 mg Aldrich pH9 buffer 50 mL Temperature 100° C.This control sample did not hydrolyze even in 48 hours

Example 13 {2-[4-(2-Carboxymethoxy-ethoxy)-phenoxy]-ethoxy}-acetic acid

To a suspension of sodium hydride (60%, 132 grams, 3.30 moles) inanhydrous dimethylformamide (600 mL) under nitrogen atmosphere at 0° C.was added hydroquinone bis ethanol (150 grams, 756.7 mmoles) in smallfor hour, later stirred at room temperature for one hour. To the abovemixture was added a solution of chloro acetic acid (195 grams, 2.06moles) in anhydrous dimethylformamide (300 mL) very cautiously drop wiseas the reaction is exothermic. Later the reaction is maintained at 80°C. for one hour and left at room temperature for 16 hours. Reactionmixture carefully poured onto ice (3 kg), extracted with ethyl acetate(2×500 mL) and organic phase discarded. The pH of the aqueous layer wasadjusted to 2 with 3N-hydrochloric acid and extracted into ethylacetate. The ethyl acetate extract was dried over sodium sulphatefollowed by distillation to yield crude 13 (120 grams, 50.5%) which wascarried over to next stage. ¹H NMR (CDCl₃) δ 3.84 (m,2H,CH₂), 4.06(m,4H,CH_(2×2)), 6.82 (s,2H,Ar).

Example 14{2-[4-(2-Chlorocarbonylmethoxy-ethoxy)-phenoxy]-ethoxy}-acetyl chloride

A mixture of {2-[4-(2-Carboxymethoxy-ethoxy)-phenoxy]-ethoxy}-aceticacid 13 (5 g) and thionyl chloride (12 mL) was refluxed for 6 hours,excess of thionyl chloride was distilled off to get crude 14, which wasused as such for next reaction.

Example 15[2-(4-{2-[5-Chloro-2-(2,4-dichloro-phenoxy)-phenoxycarbonylmethoxy]-ethoxy}phenoxy)-ethoxy]-aceticacid 5-chloro-2-(2,4-dichloro-phenoxy)-phenyl ester

To a mixture of benzene (90 mL) and triclosan sodium (9 grams, 28.89mmol) maintained at 10° C., was added dropwise a solution of acidchloride 14 in benzene. The reaction mixture was stirred at roomtemperature for 38 hours. The solids were filtered off and the benzenelayer washed with 5% sodium sulphate followed by charcoal treatment. 90%of the benzene was distilled off and the remaining solution wasprecipitated into diisopropyl ether. The precipitate was filtered off,dried and recrystallised from ethyl acetate to get pure 15 (4.5 grams)as a white powder. m.p: 132-135° C. ¹H NMR (CDCl₃) δ 3.78 (t,4H,CH₂),4.02 (t,4H,CH₂), 4.40 (s,4H,CH₂), 6.84 (s,4H,Ar), 7.00 (d,2H,Ar), 7,12(d,2H,Ar), 7.42 (m,4H,Ar), 7.52 (d,2H,Ar), 7.76 (d,2H,Ar).

Hydrolysis Dimer 500 mg Aldrich pH9 buffer 50 mL Temperature 100° C.Hydrolyzed in 6 hour 30 minutes

Alternative Preparation of Compound 15

PDO Acid Chloride

A mixture of acid 13 (10 grams, 62.40 mmol) and thionyl chloride (25 mL,342.64 mmol) was stirred at room temperature for one hour and heated toreflux for 20 hours. Excess of thionyl chloride was distilled off andtoluene (25 mL) was added, distilled off toluene and this process wasrepeated another time, to get the acid chloride 14 which was used assuch for next stage.

Dimer

To a solution of triclosan (6.19 grams, 21.37 mmol) and pyridine (2.25grams, 28.44 mmol) in chloroform (40 mL) at 0° C. under N₂ atmospherewas added a solution of acid chloride (5 grams, 14.24 mmol) inchloroform (10 mL) dropwise and stirred at the same temperature for onehour. TLC showed the presence of triclosan by around 5%, so we addedfurther quantity of acid chloride (1 gram, 2.84 mmol) and stirredfurther for 3 hours. TLC showed the presence of triclosan by around 5%.

The reaction mixture was washed with water (2×100 mL) and 5% Sodiumcarbonate (3×100 mL). It was dried over sodium sulphate, treated withCharcoal and distilled to get crude compound, which was slurried indiisopropyl ether (25 mL), filtered, dried and recrystallised from ethylacetate to get pure dimmer 15 (2.5 grams) as a white powder. m.p:127.6-129.6° C.

Hydrolysis Data Dimer 0.5 grams pH 9 buffer 50 mL Temperature 100° C.Hydrolyzed in 28 hours 30 minutes

Dimer 0.5 grams pH 9 buffer 50 mL Temperature 50° C.Hydrolyzed in 150 hours

Example 16 (4-Methoxycarbonylmethoxy-phenoxy)-acetic acid methyl ester

To a mixture of sodium hydride (60%, 92 grams, 2.3 moles) in DMF (400mL) at 0° C. was added hydroquinone (100 grams, 909 mmol) carefully andstirred for 30 minutes. Methyl chloro acetate (247 grams, 2.276 moles)was added drop wise and later stirred at room temperature for 2 hours.Reaction mixture was carefully quenched into ice water (2 lit). Crude 16was filtered, dried and recrystallised from a mixture of ethylacetate:hexane (1:6) to give pure 16 (95 grams, 41.1%) as a whitepowder. M.p: 96-98° C. ^(I)H NMR (CDCl₃) 6 3.68(s,3H,Ester),4.54(s,2H,OCH₂), 6.82(s,2H,Ar).

Example 17 (4-Carboxymethoxy-phenoxy)-acetic acid

(4-Methoxycarbonylmethoxy-phenoxy)-acetic acid methyl ester 16 (100grams, 394 mmol) was added to 3.25 M-sodium hydroxide solution (600 mL)and heated to 70° C. for 20 hours and poured onto 1 liter of ice coldwater. The pH of the solution was adjusted to 1 with concentratedhydrochloric acid. Crude 17 was filtered, dried and recrystallised fromDMF by precipitating with water to give pure 17 (60 grams, 67.4%) as awhite powder. M.p: 254-256.5° C. ^(I)H NMR (CDCl₃+DMSO,d₆) δ4.44(s,2H,OCH₂), 6.72(s,2H,Ar).

Example 18 (4-Chlorocarbonylmethoxy-phenoxy)-acetyl chloride

10 grams of (4-Carboxymethoxy-phenoxy)-acetic acid 17 was taken in tothionyl chloride (30 mL) and refluxed for 6 hours, excess of thionylchloride was distilled off to get crude 18, which was used as such fornext reaction.

Example 19{4-[5-Chloro-2-(2,4-dichloro-phenoxy)-phenoxycarbonylmethoxy]-phenoxy}-aceticacid 5-chloro-2-(2,4-dichloro-phenoxy)-phenyl ester

To a mixture of triclosan sodium in 100 ml of benzene maintained at 10°C. was added a solution of (4-Chlorocarbonylmethoxy-phenoxy)-acetylchloride 18 (5 grams) in benzene drop wise and stirred at roomtemperature over night. The TLC showed the presence of unreactedtriclosan. Further 5 grams of (4-Chlorocarbonylmethoxy-phenoxy)-acetylchloride 18 was added and refluxed over night. The TLC showed withpresence of triclosan. Thionyl chloride (30 mL) was added and refluxedfor 72 hours. The TLC showed the completion of reaction. Excess thionylchloride along with benzene was distilled off under vacuum, the productwas taken in to 50 mL ethyl acetate, washed with 5% sodium bicarbonatesolution, dried over sodium sulphate and distilled to get crude whichwas purified by column chromatography using hexane:benzene (8:2) to getpure 19 (1 gram) as a light yellow syrup.

Alternative Method of Preparation of Compound 19

To a refluxing solution of triclosan (54 grams, 186.49 mmol) and(4-Carboxymethoxy-phenoxy)-acetic acid 17 (25 grams, 110.61 mmol) intoluene (150 mL) was added a drop wise thionyl chloride (30 mL) andfurther refluxed for 24 hours. The TLC showed the presence of unreactedtriclosan. To this refluxing solution was added dimethylformamide (0.5mL) and continued reflux for additional 24 hours. The TLC showed thecompletion of reaction, excess thionyl chloride and toluene weredistilled off. The compound was dissolved in ethyl acetate (100 mL),washed with 5% Sodium bicarbonate solution, dried over sodium sulphateand distilled to get crude 19, which was purified by columnchromatography on silica gel using hexane:benzene (8:2) as eluant to getpure 19 (12 grams) as light yellow syrup.

^(I)H NMR (CDCl₃) 4.76(s,2H,CH₂), 6.79(m,2H,Ar), 6.86(d,2H,Ar), 7.22(m,3H,Ar), 7.45(d,1H,Ar).

Another Method of Preparation of Compound 19

Acid Chloride

A mixture of diacid 17 (15 grams, 66.31 mmol), Thionyl chloride (75 mL,1.027 mol) and dimethylformamide (0.5 mL) was stirred at roomtemperature for 1 hour and later heated to reflux for 20 hours. Excessof thionyl chloride was distilled off, toluene (25 mL was added,distilled off Toluene and this process was repeated another time, to getthe acid chloride 18 which was used as such for next stage.

Dimer

To a solution of triclosan (8.25 grams, 28.49 mmol) and pyridine (3grams, 37.92 mmol) in chloroform (40 mL) at 0° C. under N₂ atmospherewas added dropwise a solution of acid chloride 18 (5 grams, 19 mmol) inchloroform (10 mL) and stirred at the same temperature for 2 hours 45minutes. Reaction mass was diluted with chloroform (200 mL), washed withwater (4×100 mL), dried over sodium sulphate, given charcoal treatmentand distilled to get crude product 19 as syrup, which crystallized tosolid product in 12 hours. The product was washed with hexane (100 mL)followed by diisopropyl ether (25 mL) to get dimer 19 (7 grams) as offwhite powder. m.p: 124-131° C. A sample on recrystallization gave amelting point of 130-132° C. as a white powder

Hydrolysis Data for compound 19 under different conditions

Compound 19 0.5 grams pH 9 buffer 50 mL Temperature 100° C.Hydrolyzed in 23 hours 30 minutes

Compound 19 0.5 grams pH 9 buffer 50 mL Temperature 50° C.Hydrolyzed in 150 hours

Compound 19 0.5 grams pH 7 buffer 50 mL Temperature 50° C.By TLC it hydrolyzed around 5% in 48 hours

Compound 19 0.5 grams pH 7 buffer 50 mL Temperature 100° C.By TLC it hydrolyzed around 15% in 48 hours

Diglycolyl Chloride

A solution of diglycolic acid (25 grams, 186.44 mmol) and Thionylchloride (30 mL, 411.17) was refluxed for 5 hours. Excess thionylchloride was distilled off and the acid chloride was purified by highvacuum distillation to get pure product (25 grams, 78.6%) as a lightyellow liquid. bp: 84-87° C./2 mm Hg.

Dimer (Batch-01)

To a solution of triclosan (23 grams, 79.43 mmol) and pyridine (10.9 mL,134.91 mmol) in chloroform (110 mL) at 0° C. under N₂ atmosphere, wasadded a solution of diglycolyl chloride (11 grams, 64.33 mmol) inchloroform (15 mL) dropwise over a period of 30 minutes and stirred atthe same temperature for 2 hours. It was then placed in a refrigeratorover night. The reaction mixture was washed with water (2×100 mL), 5%Sodium bicarbonate (3×100 mL), 5% copper sulphate solution (3×100 mL)and water (2×100 mL). It was dried over sodium sulphate and thechloroform was distilled off under vacuum to get the dimer 20 (15 grams,) as a yellow thick syrup. ^(I)H NMR (CDCl₃) δ 4.44(s,2H,CH₂),6.80(d,1H,Ar), 6.89(d,2H,Ar), 7.20 (m,3H,Ar), 7.43(d,1H,Ar).

Dimer (Batch-02)

To a solution of triclosan (16.7 grams, 57.67 mmol) and pyridine (9 mL,111.39 mmol) in chloroform (100 mL) at 0° C. under N₂ atmosphere, wasadded a solution of diglycolyl chloride (9 grams, 52.63 mmol) inchloroform (10 mL) drop wise over a period of 30 minutes and stirred atthe same temperature for 2 hours. The reaction mixture was washed withwater (2×100 mL), 5% Sodium bicarbonate (3×100 mL), 5% copper sulphatesolution (3×100 mL), water (2×100 mL). It was dried over sodium sulphateand the chloroform was distilled off under vacuum to get the dimer (15grams,) as a yellow thick syrup, which on standing for two dayssolidified. This solid was slurred in hexane (50 mL) to get the crudedimer 20 (9 grams) as brown powder.

Purification: 14 grams of crude dimer dissolved in chloroform (100 mL)washed with 5% sodium bicarbonate solution (3×100 mL), water (2×100 mL),dried over sodium sulphate, treated with activated carbon, distilled off90% chloroform and precipitated with diisopropyl ether, cooled to 10°C., filtered and dried to get the pure dimmer 20 (7.6 grams) as whitepowder. Mp: 84.8-86.5° C. ^(I)H NMR (CDCl₃) δ 4.44(s,2H,CH₂),6.80(d,1H,Ar), 6.89(d,2H,Ar), 7.20 (m,3H,Ar), 7.43(d,1H,Ar).

Hydrolysis Dimer 0.5 grams pH 9 buffer 50 mL Temperature 100° C.Hydrolyzed in 25 hours

Dimer 0.5 grams pH 9 buffer 50 mL Temperature 50° C.Hydrolyzed in 102 hours

Dimer 0.5 grams pH 7 buffer 50 mL Temperature 100° C.Hydrolyzed 50% only in 53 hours

Example 21 Synthesis of Compound 21 (a) Synthesis ofBenzyl-6-bromohexanoate

Into a clean and dry 3 liter, 3 necked round bottom flask equipped witha desiccant tube was added 250 grams of benzyl alcohol, 496 grams of6-bromohexanoic acid, 1500 ml of toluene and 10 grams of p-toluenesulphonic acid. The flask was left with stirring in an oil bathmaintained at 140° C. for one hour when all the starting materialdisappeared as determined by thin layer chromatography. The reactionmixture was cooled to room temperature and washed with 5% solution ofsodium bicarbonate followed by water. The toluene layer was dried usingsodium sulphate and the toluene was distilled off using high vacuumdistillation to yield 540 grams of colorless benzyl-6-bromohexanoatewith a boiling point of 160° C. and a purity of 99% as determined by gaschromatography.

(b) Addition of benzyl-6-bromohexanoate on diglycolic acid

Into a clean and dry 2 liter, 3 necked round bottom flask equipped witha desiccant tube was added 100 grams of diglycolic acid in 1 liter ofacetone. 310 ml of anhydrous trimethylamine was added to this solutionand stirred at room temperature for about 10 minutes. To this stirringsolution was added dropwise 436 grams of benzyl-6-bromohexanoate. Theflask was left with stirring at room temperature for 24 hours followingwhich the reaction mixture was precipitated in cold water followed byextraction using ethyl acetate. The ethyl acetate layer was washed with5% solution of sodium bicarbonate followed by drying using sodiumsulphate. Ethyl acetate was distilled off using high vacuum distillationto yield 257 grams of colorless liquid 21.

Example 22 Synthesis of Diglycolic Acid Dicaproic Acid

Into a hydrogenation apparatus was added 250 grams of 21 dissolved in500 ml of Ethyl acetate. 2 grams of 10% Palladium on Carbon was added tothe solution and the resulting reaction mixture in the pressure vesselwas purged with hydrogen maintained at a pressure of 4 kg and stirredfor 16 hours. The completion of reaction was determined by disappearanceof starting material using thin layer chromatography. The reactionmixture after completion was filtered using the high flow bed and washedwith ethyl acetate. Ethyl acetate was distilled off to yield 250 gramsof crude 22. The resulting crude product was purified viacrystallization using a mixture of ethyl acetate and hexane to yield 185grams of pure 22 with a melting point of 74-76° C.

Example 23 Synthesis of Diglycolic Acid Dicaproic Acid Chloride

A clean and dry 250 ml round bottom flask equipped with a nitrogen inletwas charged with 50 grams of diglycolic acid dicaproic acid 22 and 70 mlof thionyl chloride. The flask was left for stirring at 80° C. for 24hours following which thionyl chloride was distilled under vacuum. 60 mlof toluene was added to the reaction mixture and any remaining thionylchloride was distilled off the reaction mixture along with toluene underhigh vacuum to yield 45 grams of light yellow colored acid chloride 23.

Example 24 Synthesis of Dimer of Triclosan From Diglycolic AcidDicaproic Acid Chloride

Into a clean and dry 1 liter, 3 necked round bottom flask equipped witha nitrogen inlet was added 37.7 grams of triclosan in 200 ml ofchloroform. 16 ml of pyridine was added to the reaction mixture and thereaction mixture was cooled to 0° C. along with stirring. To thisstirring solution was added dropwise 45 grams of diglycolic aciddicaproic acid chloride 23 dissolved in 50 ml of chloroform and thereaction was left for stirring at 0° C. for two hours following whichthe reaction mixture was precipitated in cold water followed byextraction using ethyl acetate. The ethyl acetate layer was washed with5% solution of sodium bicarbonate followed by 1% solution of coppersulphate and the ethyl acetate fraction was dried using sodium sulphate.Ethyl acetate was distilled off using high vacuum distillation and thecrude compound was purified using column chromatography to yield 35grams of light yellow colored syrup of dimer 24.

Example 25 Synthesis of Benzyl Glycolate Stearate

Into a clean and dry 2 liter, 3 necked round bottom flask equipped witha desiccant tube was added 100 grams of stearic acid in 500 ml ofdimethylformamide. 100 ml of anhydrous triethylamine was added to thissolution and stirred at room temperature for about 10 minutes. To thisstirring solution was added dropwise 80 grams of benzylchloroacetate.The flask was left for stirring at room temperature for 24 hoursfollowing which the reaction mixture was precipitated in cold waterfollowed by extraction using ethyl acetate. The ethyl acetate layer waswashed with 5% solution of sodium bicarbonate followed by drying usingsodium sulphate. Ethyl acetate was distilled off using high vacuumdistillation to yield 150 grams of crude 25. Crude 25 was purified bycolumn chromatography using hexane as an eluant to yield 92 grams ofpure 25 as a low melting white solid.

Example 26 Synthesis of 2-hydroxy acetic acid stearate

Into a hydrogenation apparatus was added 250 grams of 25 dissolved in500 ml of Ethyl acetate. 2 grams of 10% Palladium on Carbon was added tothe solution and the resulting reaction mixture in the pressure vesselwas purged with hydrogen maintained at a pressure of 4 kg and stirredfor 16 hours. The completion of reaction was determined by disappearanceof starting material using thin layer chromatography. The reactionmixture after completion was filtered using the high flow bed and washedwith ethyl acetate. Ethyl acetate was distilled off to yield 250 gramsof crude 26. The resulting crude product was purified viacrystallization using a mixture of ethyl acetate and hexane to yield 185grams of pure 26 with a melting point of 74-76° C.

Example 27 Synthesis of Stearic Acid Glycolic Acid Chloride

A clean and dry 250 ml round bottom flask equipped with a nitrogen inletwas charged with 25 grams of glycolic acid stearate 26 and 30 ml ofthionyl chloride. The flask was left for stirring along with refluxingfor 24 hours following which thionyl chloride was distilled undervacuum. 60 ml of toluene was added to the reaction mixture and anyremaining thionyl chloride was distilled off the reaction mixture alongwith toluene under high vacuum to yield 24 grams of light yellow coloredacid chloride 27, which was used as such in the next synthetic step.

Example 28 Synthesis of Triclosan Glycolic Acid Stearate

Into a clean and dry 1 liter, 3 necked round bottom flask equipped witha nitrogen inlet was added 15 grams of triclosan in 150 ml of ethylacetate. 15 ml of pyridine was added to the reaction mixture and thereaction mixture was left for stirring at room temperature for 10minutes. To this stirring solution was added dropwise 24 grams ofstearic acid glycolic acid chloride 27 dissolved in 30 ml of ethylacetate and the reaction was left for stirring at room temperature fortwenty four hours following which the triethylamine hydrochloride saltwas filtered off and the ethyl acetate layer was washed with 5% solutionof sodium bicarbonate followed by drying using sodium sulphate. Ethylacetate was distilled off using high vacuum distillation to yield 22grams of crude 28. Complete hydrolytic degradation of 500 mg oftriclosan glycolic acid stearate in 50 ml of pH 9.0 at 100° C. occurredin 27 hours.

Example 29 Synthesis of Dibenzyl Diglycolyl Diglycolate (a) Synthesis ofBenzyl Chloroacetate

Into a clean and dry 3 liter, 3 necked round bottom flask equipped witha desiccant tube was added 420 grams of benzyl alcohol, 440 grams ofchloroacetic acid, 2000 ml of toluene and 10 grams of p-toluenesulphonic acid. The flask was left with stirring in an oil bathmaintained at 140° C. for one hour when all the starting materialdisappeared as determined by thin layer chromatography. The reactionmixture was cooled to room temperature and washed with 5% solution ofsodium bicarbonate followed by water. The toluene layer was dried usingsodium sulphate and the toluene was distilled off using high vacuumdistillation to yield 560 grams of colorless benzylchloroacetate with apurity of 99% as determined by gas chromatography.

(b) Reaction of Diglycolic Acid with Benzyl Chloroacetate

Into a clean and dry 2 liter, 3 necked round bottom flask equipped witha desiccant tube was added 40 grams of diglycolic acid in 200 ml ofacetone. 125 ml of anhydrous triethylamine was added to this solutionand stirred at room temperature for about 10 minutes. To this stirringsolution was added dropwise 127 grams of benzylchloroacetate. The flaskwas left for stirring at room temperature for 24 hours following whichthe reaction mixture was precipitated in cold water followed byextraction using ethyl acetate. The ethyl acetate layer was washed with5% solution of sodium bicarbonate followed by drying using sodiumsulphate. Ethyl acetate was distilled off using high vacuum distillationand the compound was precipitated in hexane to yield 108 grams of pure29 with a melting point of 59-60° C.

Example 30 Synthesis of Diglycolic Acid Diglycolate

Into a hydrogenation apparatus was added 90 grams of 29 dissolved in 250ml of ethyl acetate. 15 grams of 10% palladium on carbon was added tothe solution and the resulting reaction mixture in the pressure vesselwas purged with hydrogen maintained at a pressure of 4 kg and stirredfor 16 hours. The completion of reaction was determined by disappearanceof starting material using thin layer chromatography. The reactionmixture after completion was filtered using the high flow bed and washedwith ethyl acetate. Ethyl acetate was distilled off to yield 48 grams ofcrude 30. The resulting crude product was purified via crystallizationusing a mixture of ethyl acetate and hexane to yield 35 grams of pure 30with a melting point of 100-102° C.

Example 31 Synthesis of Diglycolic Acid Diglycolyl Chloride

A clean and dry 250 ml round bottom flask equipped with a nitrogen inletwas charged with 30 grams of diglycolic acid diglycolate 30 and 150 mlof thionyl chloride. The flask was left for stirring along withrefluxing for 24 hours following which thionyl chloride was distilledunder vacuum. 60 ml of toluene was added to the reaction mixture and anyremaining thionyl chloride was distilled off the reaction mixture alongwith toluene under high vacuum to yield 30 grams of light yellow coloredacid chloride 31 that was used as such in the next synthetic step.

Example 32 Synthesis of Triclosan Dimer From Diglycolic Acid DiglycolylChloride

Into a clean and dry 1 liter, 3 necked round bottom flask equipped witha nitrogen inlet was added 31 grams of triclosan in 200 ml ofchloroform. 12 ml of pyridine was added to the reaction mixture and thereaction mixture was cooled to 0° C. along with stirring. To thisstirring solution was added dropwise 20 grams of diglycolic aciddiglycolyl chloride 31 dissolved in 50 ml of chloroform and the reactionwas left for stirring at 0° C. for two hours following which thereaction mixture was left for stirring overnight. The reaction mixturewas precipitated in cold water. The chloroform layer was washed with 5%solution of sodium bicarbonate followed by drying using sodium sulphate.Chloroform was distilled off using high vacuum distillation and thecrude compound was purified using column chromatography to yield 40grams of light yellow colored syrup of dimer 32 with 92% purity asdetermined by HPLC.

When any variable occurs more than one time in any constituent or in anyformula, its definition in each occurrence is independent of itsdefinition at every other occurrence. Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

It is believed the chemical formulas and names used herein correctly andaccurately reflect the underlying chemical compounds. However, thenature and value of the present invention does not depend upon thetheoretical correctness of these formulae, in whole or in part. Thus itis understood that the formulas used herein, as well as the chemicalnames attributed to the correspondingly indicated compounds, are notintended to limit the invention in any way, including restricting it toany specific tautomeric form or to any specific optical or geometricisomer, except where such stereochemistry is clearly defined.

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included.

The disclosures of each patent, patent application and publication citedor described in this document are hereby incorporated herein byreference, in their entireties.

Those skilled in the art will appreciate that numerous changes andmodifications maybe made to the preferred embodiments of the inventionand that such changes and modifications maybe made without departingfrom the spirit of the invention. It is, therefore, intended that theappended claims cover all such equivalent variations as fall within thetrue spirit and scope of the invention.

1. A functionalized triclosan oligomer of formula A, B, or C:R[(CH₂)_(f)C(═O)—(Y)_(a)—O—R¹]_(w)   A;R[—(Y)_(a)—O—R¹]_(w)   B;R¹—O—(Y¹)_(c)—O—(Y)_(d)—O—R¹   C; wherein: each Y is independently:—OCH₂C(═O)— (inverse glycolic ester moiety), —OCH(CH₃)C(═O)— (inverselactic ester moiety), —OCH₂CH₂OCH₂C(═O)— (inverse dioxanone estermoiety), —OCH₂CH₂CH₂CH₂CH₂C(═O)— (inverse caprolactone ester moiety),—O(CH₂)_(y)C(═O)—, or —O(CH₂CH₂O)₂OCH₂C(═O)—; each Y¹ is independently:—C(═O)CH₂O— (glycolic ester moiety), —C(═O)CH(CH₃)O— (lactic estermoiety), —C(═O)CH₂OCH₂CH₂O— (dioxanone ester moiety),—C(═O)CH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety), —C(═O)(CH₂)_(m)O—,or —C(═O)CH₂O(CH₂CH₂O)_(n)—; R is a di-, tri, tetra-, penta- orhexaradical derived from C₁₋₂₅ alkyl, aryl, or aryl-(C₁₋₆alkyl)₁₋₃-,wherein from 1-4 of the CH₂ groups within the alkyl chain are optionallyindependently replaced by O or S atoms, preferably by O atoms, such thateach of said O or S atoms is attached only to carbon atoms in the alkylchain, with the proviso that the O or S atoms are separated from thedi-, tri, tetra-, penta- or hexaradical chain ends by at least onecarbon atom and that multiple O or S atoms in the di-, tri, tetra-,penta- or hexaradical chain must be separated from each other by atleast two carbon atoms; or R is —[CH₂CH₂O—]_(p)—, wherein p is aninteger from about 10 to about 50; R¹ is:

each a is independently an integer from about 1 to about 8; each f isindependently the integer 0 or 1; with the proviso that when f is 0,then R is other than —[CH₂CH₂O—]_(p)—; each m and n is independently aninteger from about 2 to about 24; w is an integer from about 2 to about6; and c and d are each an integer from 1 to 5, with the proviso thatthe sum of c+d is an integer from about 2 to about
 6. 2. Afunctionalized triclosan monomer of Formula I:

wherein: each Y¹ is independently: —C(═O)CH₂O— (glycolic ester moiety),—C(═O)CH(CH₃)O— (lactic ester moiety), —C(═O)CH₂OCH₂CH₂O— (dioxanoneester moiety), —C(═O)CH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety),—C(═O)(CH₂)_(m)O—, or —C(═O)CH₂O(CH₂CH₂O)_(n)—; R¹ is:

a is an integer from about 2 to about 8; and each m and n isindependently an integer from about 2 to about
 24. 3. A functionalizedtriclosan monomer of Formula II:

wherein: each X¹ is independently: —CH₂C(═O)O— (glycolic acid moiety),—CH(CH₃)C(═O)O— (lactic acid moiety), —CH₂CH₂OCH₂C(═O)O— (dioxanonemoiety), —CH₂CH₂CH₂CH₂CH₂C(═O)O— (caprolactone moiety),—(CH₂)_(y)C(═O)O—, or —(CH₂CH₂O)₂CH₂C(═O)O—; R¹ is:

a is an integer from about 2 to about 8; and each y and z isindependently an integer from about 2 to about
 24. 4. A functionalizedtriclosan monomer of Formula III:

wherein: each Y¹ is independently: —C(═O)CH₂O— (glycolic ester moiety),—C(═O)CH(CH₃)O— (lactic ester moiety), —C(═O)CH₂OCH₂CH₂O— (dioxanoneester moiety), —C(═O)CH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety),—C(═O)(CH₂)_(m)O—, or —C(═O)CH₂O(CH₂CH₂O)_(n)—; R¹ is:

b is an integer from about 2 to about 8; each m and n is independentlyan integer from about 2 to about 24; and Q is F, Cl, Br, or I.
 5. Afunctionalized triclosan oligomer of Formula IV:

wherein: each Y is independently: —OCH₂C(═O)— (inverse glycolic estermoiety), —OCH(CH₃)C(═O)— (inverse lactic ester moiety),—OCH₂CH₂OCH₂C(═O)— (inverse dioxanone ester moiety),—OCH₂CH₂CH₂CH₂CH₂C(═O)— (inverse caprolactone ester moiety),—O(CH₂)_(m)C(═O)—, or —O(CH₂CH₂O)_(n)OCH₂C(═O)—; each Y¹ isindependently: —C(═O)CH₂O— (glycolic ester moiety), —C(═O)CH(CH₃)O—(lactic ester moiety), —C(═O)CH₂OCH₂CH₂O— (dioxanone ester moiety),—C(═O)CH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety), —C(═O)(CH₂)_(m)O—,or —C(═O)CH₂O(CH₂CH₂O)_(n)—; R¹ is:

a and b are each independently an integer from about 1 to about 8; eachm and n is independently an integer from about 2 to about
 24. 6. Afunctionalized triclosan oligomer of formula V:

wherein: each Y is independently: —OCH₂C(═O)— (inverse glycolic estermoiety), —OCH(CH₃)C(═O)— (inverse lactic ester moiety),—OCH₂CH₂OCH₂C(═O)— (inverse dioxanone ester moiety),—OCH₂CH₂CH₂CH₂CH₂C(═O)— (inverse caprolactone ester moiety),—O(CH₂)_(m)C(═O)—, or —O(CH₂CH₂O)_(n)OCH₂C(═O)—; each Y¹ isindependently: —C(═O)CH₂O— (glycolic ester moiety), —C(═O)CH(CH₃)O—(lactic ester moiety), —C(═O)CH₂OCH₂CH₂O— (dioxanone ester moiety),—C(═O)CH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety), —C(═O)(CH₂)_(m)O—,or —C(═O)CH₂O(CH₂CH₂O)_(n)—; R is a diradical derived from C₁₋₂₅ alkyl,aryl, or aryl-(C₁₋₆alkyl)₁₋₃-, wherein from 1-4 of the CH₂ groups withinthe alkyl chain are optionally independently replaced by O or S atoms,preferably by O atoms, such that each of said O or S atoms is attachedonly to carbon atoms in the alkyl chain, with the proviso that the O orS atoms are separated from the diradical chain ends by at least onecarbon atom and that multiple O or S atoms in the diradical chain mustbe separated from each other by at least two carbon atoms; or R is—[CH₂CH₂O—]_(p)-, wherein p is an integer from about 10 to about 50; R¹is:

each b is independently an integer from about 0 to about 8; and each mand n is independently an integer from about 2 to about
 24. 7. Afunctionalized triclosan oligomer of Formula VI:

wherein: each X is independently: —OC(═O)CH₂— (inverse glycolic acidmoiety), —OC(═O)CH(CH₃)— (inverse lactic acid moiety),—OC(═O)CH₂OCH₂CH₂— (inverse dioxanone acid moiety),—OC(═O)CH₂CH₂CH₂CH₂CH₂— (inverse caprolactone acid moiety),—OC(═O)(CH₂)_(y)—, or —OC(═O)CH₂(OCH₂CH₂)_(z)—. each X¹ isindependently: —CH₂C(═O)O— (glycolic acid moiety), —CH(CH₃)C(═O)O—(lactic acid moiety), —CH₂CH₂OCH₂C(═O)O— (dioxanone moiety),—CH₂CH₂CH₂CH₂CH₂C(═O)O— (caprolactone moiety), —(CH₂)_(y)C(═O)O—, or—(CH₂CH₂O)₂CH₂C(═O)O—; R is a diradical derived from C₁₋₂₅ alkyl, aryl,or aryl—(C₁₋₆alkyl)l₁₋₃-, wherein from 1-4 of the CH₂ groups within thealkyl chain are optionally independently replaced by O or S atoms,preferably by O atoms, such that each of said O or S atoms is attachedonly to carbon atoms in the alkyl chain, with the proviso that the O orS atoms are separated from the diradical chain ends by at least onecarbon atom and that multiple O or S atoms in the diradical chain mustbe separated from each other by at least two carbon atoms; or R is—[CH₂CH₂O—]_(p)—, wherein p is an integer from about 10 to about 50; orR is a homopolymer or copolymer of glycolide, lactide, caprolactone,p-dioxanone, or a combination thereof (e.g., M, of from 100, 200, 300,400, 500, 600, 700, 800, 900, to 1000); R¹ is:

each a is independently an integer from about 0 to about 8; and each yand z is independently an integer from about 2 to about 24; with theproviso that when R is a diradical derived from C₁₋₂₅ alkyl, aryl, oraryl—(C₁₋₆alkyl)₁₋₃-, wherein none of the CH₂ groups within the alkylchain are replaced by O or S atoms, then at least one of a is an integerfrom about 1 to about
 8. A functionalized triclosan oligomer of formulaVII:

wherein: R¹ is:


9. A functionalized triclosan oligomer of formula VIII:

wherein: Z is selected from —CH₂—CH₂—, —CH₂—O—CH₂—, and —CH₂—; and R¹is:

R is a diradical derived from C₁₋₂₅ alkyl, aryl, oraryl-(C₁₋₆alkyl)l₁₋₃-, wherein from 1-4 of the CH₂ groups within thealkyl chain are optionally independently replaced by O or S atoms,preferably by O atoms, such that each of said O or S atoms is attachedonly to carbon atoms in the alkyl chain, with the proviso that multipleheteroatoms must be separated from each other by at least two carbonatoms and from the diradical chain ends by at least one carbon atom; orR is —[CH₂CH₂O—]_(p)—, wherein p is an integer from about 10 to about50; with the proviso that at least one of Z is —CH₂—O—CH₂—.
 10. Afunctionalized triclosan oligomer of formula IX:

wherein: R′ and R″ are each independently R is a diradical derived fromC₁₋₂₅ alkyl, aryl, or aryl—(C₁₋₆alkyl)₁₋₃-, wherein from 1-4 of the CH₂groups within the alkyl chain are optionally independently replaced by Oor S atoms, such that each of said O or S atoms is attached only tocarbon atoms in the alkyl chain, with the proviso that multipleheteroatoms must be separated from each other by at least two carbonatoms and from the diradical chain ends by at least one carbon atom; orR is —[CH₂CH₂O—]_(p)—, wherein p is an integer from about 10 to about50; and R is:


11. A functionalized triclosan monomer according to claim 3, selectedfrom the group consisting of:


12. A functionalized triclosan oligomer according to claim 1 having thestructure:


13. A medical device or medical device coating, comprising: afunctionalized triclosan monomer according to claim 2, 3, 4, or
 11. 14.The medical device or medical device coating according to claim 13,wherein the device or coating is selected from a surgical suturecoating, staple coating, orthopedic device coating, fabric coating,surgical mesh coating, clip coating, stent coating, needle coating,catheter, and catheter coating.
 15. A composition, comprising afunctionalized triclosan monomer according to claim 2, 3, 4, or 11,wherein the composition is selected from an oral composition, home carecomposition, anti-tartar dental product, antimicrobial fabric,antimicrobial flush solution, chewing gum composition, soap composition,toothpaste composition, flowable personal care or cleaning composition,and a pharmaceutical composition.
 16. A medical device or medical devicecoating, comprising: a functionalized triclosan oligomer according toclaim 1, 5, 6, 7, 8, 9, 10, or
 12. 17. The medical device or medicaldevice coating according to claim 16, wherein the device or coating isselected from a surgical suture coating, staple coating, orthopedicdevice coating, fabric coating, surgical mesh coating, clip coating,stent coating, needle coating, catheter, and catheter coating.
 18. Acomposition, comprising a functionalized triclosan oligomer of claim 1,5, 6, 7, 8, 9, 10, or 12, wherein the composition is selected from anoral composition, home care composition, anti-tartar dental product,antimicrobial fabric, antimicrobial flush solution, chewing gumcomposition, soap composition, toothpaste composition, flowable personalcare or cleaning composition, and a pharmaceutical composition.
 19. Adi-, tri-, or polyamido compound that is the reaction product of afunctionalized triclosan oligomer of formula VII:

wherein: R¹ is:

a biodegradable di- tri-, or polyamine.
 20. A di-, tri-, or polyamidocompound according to claim 19, wherein the biodegradable di- tri-, orpolyamine is selected from the group consisting of:

wherein n is an integer from about 10 to about 50;


21. A di-, tri-, or polyamido compound that is the reaction product of adiacid selected from the group consisting of:

a di- tri-, or polyamine is selected from the group consisting of:

wherein n is an integer from about 10 to about 50;


22. A composition comprising: 1) a functionalized triclosan monomer offormula III:

wherein: each Y¹ is independently: —C(═O)CH₂O— (glycolic ester moiety),—C(═O)CH(CH₃)O— (lactic ester moiety), —C(═O)CH₂OCH₂CH₂O— (dioxanoneester moiety), —C(═O)CH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety),—C(═O)(CH₂)_(m)O—, or —C(═O)CH₂O(CH₂CH₂O)_(n)—; R¹ is:

b is an integer from about 1 to about 8; each m and n is independentlyan integer from about 2 to about 24; and Q is F, Cl, Br, or I; and 2) anamine acid selected from the group consisting of:


23. A medical device or medical device coating, comprising: a di-, tri-,or polyamido compound according to claim 19 or
 21. 24. A medical deviceaccording to claim 13, wherein the device is implantable.
 25. A medicaldevice according to claim 16, wherein the device is implantable.
 26. Amedical device according to claim 23, wherein the device is implantable.27. A controlled drug delivery system characterized by at least onepolymer composition comprising a functionalized triclosan monomeraccording to claim 2, 3, 4, or 11, wherein said polymer composition isphysically admixed with a biologically or pharmacologically activeagent.
 28. A controlled drug delivery system characterized by at leastone polymer composition comprising a functionalized triclosan oligomeraccording to claim 1, 5, 6, 7, 8, 9, 10, or 12, wherein said polymercomposition is physically admixed with a biologically orpharmacologically active agent.
 29. A controlled drug delivery systemcharacterized by at least one polymer composition comprising a di-,tri-, or polyamido compound according to claim 19 or 21, wherein saidpolymer composition is physically admixed with a biologically orpharmacologically active agent.